Microtubules are cytoskeleton protein polymers comprised of α-tubulin and β-tubulin polymers. They are vital components of all cells and are critical for the maintenance of cell morphology. Microtubules form the basis of the mitotic apparatus in cells, and dynamically functioning microtubules are critical for normal cell division, as well as cell movement and attachment. Interference with microtubule dynamics prevents dividing cells from proceeding normally through the cell cycle and leads to G2/M cell cycle arrest and apoptosis. Cancer cells acquire unlimited replicative potential and continually divide without going into quiescence or senescence. As a result, cancer cells are extremely dependent upon microtubule dynamics and thus are susceptible to agents that interfere with microtubule dynamics either through inhibiting tubulin polymerization or stabilizing microtubule polymers.
During the M-phase of the cell cycle, the dynamic microtubules that comprise the cell mitotic spindle are the target of most of the known tubulin-directed agents. Although the ultimate mechanism of action of the various anti-mitotic agents is essentially the same (i.e. disruption of normal microtubule formation and dynamics), there are differences in the activity of the various agents against different cancer types. For example, the vinca alkaloids (such as vincristine, vinblastine, and vinorelbine) are generally more efficacious against hematological cancers and less effective against solid tumors, though vinorelbine has activity in non-small cell lung cancer and breast cancer; while the taxanes (such as paclitaxel and docetaxel) are effective against ovarian, breast and lung solid tumors, but are relatively ineffective against solid tumors of the colon and kidney and against hematological cancers.
It would be desirable to develop compounds that are potent inhibitors of tubulin polymerization as anticancer agents.
US Patent Application Publication No. US 2005/0085531 (Amphora) discloses 544 thiophene-based compounds said to exhibit ATP-utilizing enzyme inhibitory activity. These compounds include 4-amino-5-benzoyl-2-[(2-methoxyphenyl)amino]thiophene-3-carbonitrile, said to be an inhibitor of GSK-3α, GSK-3β, KIT, and MAPKAPK; 4-amino-5-benzoyl-2-(phenylamino)thiophene-3-carboxamide, said to be an inhibitor of Aurora-A, GSK-3α, GSK-3β, and KIT; and 4-amino-2-(1,3-benzodioxol-5-ylamino)-5-(4-chlorobenzoyl)thiophene-3-carboxamide (compound 27A below), said to be an inhibitor of Aurora-A, GSK-3α, and GSK-3β. No specific activities are given, though the compounds are said to have an activity for each of the listed target enzymes greater than 3σ from the mean activity for the population of predominately inactive compounds for the same target enzyme.
US Patent Application Publication No. US 2006/0041006 (Plexxikon) discloses 281 thiophene-based compounds said to be ligands for phosphodiesterase (PDE) 4B, and their use in treating PDE4B-mediated conditions. These compounds include 43 4-amino-5-benzoyl-2-(phenylamino)thiophene-3-carbonitriles, including 4-amino-5-(2,4-dimethoxybenzoyl)-2-[(4-methoxyphenyl)amino]thiophene-3-carbonitrile (compound 7A below), and one 4-amino-5-benzoyl-2-(phenylamino)thiophene-3-carboxamide.
Graschenkova et al., Farmatsevtichnii Zhurnal, 4, 69-73 (2007), is said to disclose the synthesis and hypolipidemic activity of various 2-aroyl-3-amino-4-nitryl-5-arylamino-thiophenes. According to the abstract and indexing from Chemical Abstracts, the compound 4-amino-5-(4-chlorobenzoyl)-2-[(4-ethylphenyl)amino]thiophene-3-carbonitrile (compound 15A below) was said to be disclosed.
A number of substituted 4-amino-5-benzoyl-2-(phenylamino)thiophene-3-carbonitriles and 4-amino-5-benzoyl-2-(phenylamino)thiophene-3-carboxamides, including compounds 1A, 4A, 12A, 17A, and 38A below, are available from scientific catalogs.
The entire disclosures of all of the documents referred to in this application are incorporated into this application by reference.